This IPCP proposal is a continuation of an NCDDG Program Project grant that has been funded since April 1996. The long-term goal of our program is to explore the potential of xenogeneic (porcine) thymic transplantation to augment immune reconstitution in HIV-1-infected people showing incomplete reconstitution in the presence of HAART. We have demonstrated that porcine thymic xenografts can support human thymopoiesis and protect human thymocytes from HIV-1 induced destruction in immunodeficient mice. In conditioned normal mice, murine T cells emerging from porcine thymus grafts mediate effective recipient-restricted responses and clear opportunistic pathogens. Primate studies indicate that host conditioning is required to avoid rejection of xenogeneic thymus grafts, even in the presence of advanced SIV disease. Porcine thymic engraftment and function have been demonstrated in large animals, and partial reconstitution of naive CD4 cells has been achieved in conditioned primates receiving porcine thymus grafts. In the IPCP application, Project 1 will further examine the immune function and HIV resistance of human T cells developing in porcine thymic grafts in immunodeficient mice. Project 2 will investigate the optimal host conditioning, thymic transplantation site, and age of porcine thymic donors, for achievement of optimal immune restoration in normal primates. Project 3 will adapt this information in SIV-infected primates. These two projects are closely interrelated, and build on information on the thymic donor age, host conditioning, optimal site and method of grafting, effects of natural antibodies and of adding porcine hematopoietic cells, obtained in all projects in the NCDDG grant. The administrative Core (A) will coordinate the Program Project. These Projects constitute a highly integrated pre-clinical and clinical program aimed at thymic xenotransplantation as an approach to achieving immune reconstitution in the treatment of HIV-infected people.